Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001354803.2:c.176T>C

CA367398764

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 14308ead-6fe4-4f40-9c9b-97a88a082693

HGVS expressions

NM_001354803.2:c.176T>C

NC_000007.14:g.44145608A>G

CM000669.2:g.44145608A>G

NC_000007.13:g.44185207A>G

CM000669.1:g.44185207A>G

NC_000007.12:g.44151732A>G

NG_008847.1:g.48816T>C

NG_008847.2:g.57563T>C

ENST00000395796.8:c.*1140T>C

ENST00000616242.5:c.*262T>C

ENST00000683378.1:n.368T>C

ENST00000336642.9:c.176T>C

ENST00000345378.7:c.1145T>C

ENST00000403799.8:c.1142T>C

ENST00000671824.1:c.1205T>C

ENST00000672743.1:n.154T>C

ENST00000673284.1:c.1142T>C

ENST00000336642.8:n.194T>C

ENST00000345378.6:c.1145T>C

ENST00000395796.7:c.1139T>C

ENST00000403799.7:c.1142T>C

ENST00000437084.1:c.1091T>C

ENST00000459642.1:n.522T>C

ENST00000616242.4:n.1139T>C

NM_000162.3:c.1142T>C

NM_033507.1:c.1145T>C

NM_033508.1:c.1139T>C

NM_000162.4:c.1142T>C

NM_001354800.1:c.1142T>C

NM_001354801.1:c.131T>C

NM_001354802.1:c.2T>C

NM_001354803.1:c.176T>C

NM_033507.2:c.1145T>C

NM_033508.2:c.1139T>C

NM_000162.5:c.1142T>C

NM_033507.3:c.1145T>C

NM_033508.3:c.1139T>C

Pathogenic

PP4_Moderate PM2_Supporting PP1_Strong PS4 PP3 PP2

PS3

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 381 (p.(Met381Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal lab contributors). At least 5 of these individuals have a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors). In summary, the c.1142T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4_Moderate, PS4, PP2, PP3, PM2_Supporting.

PP4_Moderate

This variant was identified in at least 5 individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP1_Strong

This variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors).

PS4

This variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2).

PS3

While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192).

Approved on: 2023-07-17

Published on: 2023-07-17

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